BACKGROUND: Circulating tumor cells (CTCs) are thought to be an ideal surrogate marker to monitor disease progression in metastatic breast cancer (MBC). We investigated the prediction of treatment response in CTCs of MBC patients on the basis of the expression of 46 genes. METHODS: From 45 MBC patients and 20 healthy donors (HD), 2 × 5 mL of blood was collected at the time of disease progression (TP0) and at 2 consecutive clinical staging time points (TP1 and TP2) to proceed with the AdnaTest (QIAGEN). Patients were grouped into (a) responder (R) and non-responder (NR) at TP1 and (b) overall responder (OR) and overall non-responder (ONR) at TP2. A 46-gene PCR assay was used for preamplification and high-throughput gene expression profiling. Data were analyzed by use of GenEx (MultiD) and SAS. RESULTS: The CTC positivity was defined by the four-gene signature (, , , positivity). Fourteen genes were identified as significantly differentially expressed between CTC+ and CTC- patients (, , , , , , , , , , , , , and ). was highly expressed in CTC+ patients and in the NR at TP1. A significant differential expression of 4 genes (, , , and ) was observed between OR and ONR when stratifying the samples into CTC+ or CTC-. CONCLUSIONS: could be a key marker in distinguishing R from NR, and was powerful in identifying CTCs.